DESCRIPTION: (Adapted from the applicant's Description) Self-injurious behavior (SIB) is a devastating dysfunction that is expressed in highly stereotyped manners by individuals with a variety of genetic and developmental disorders (e.g., Lesch-Nyhan syndrome, autism, intellectual handicaps). The most severe expression of SIB generally occurs in Lesch-Nyhan syndrome, a disorder of purine metabolism that results in altered adenosine and dopamine neurotransmission. A variety of animal models exist in which developmental and neurochemical manipulations result in SIB. One model is the chronic methylxanthine model, in which caffeine (an adenosine receptor antagonist) is administered to rats for 10 to 12 days. A second model consists of chronic administration of pemoline (an indirect dopamine agonist) for four to eight days. Both of these manipulations result in self-injury, but the phenomenology of the behavior that is expressed is very different between these two animal models. Pemoline-treated rats exhibit profound stereotypy (repetitive, apparently purposeless behavior) prior to onset of SIB, and the principle expression of SIB is stereotyped paw-biting. Caffeine-treated rats do not express high levels of stereotypy prior to onset of SIB, and the predominant form of SIB expressed by these rats is stereotypic gnawing on the tail until it is pink and raw. The differences in etiology and expression of SIB during chronic administration of caffeine and pemoline suggest that differing neurochemical adaptations may underlie these phenomenologically-distinct behavioral outcomes. The present experiments are designed to characterize adaptations in adenosinergic and dopaminergic neurotransmission that develop during chronic administration of caffeine and pemoline. Caffeine and pemoline will be administered to independent groups of rats until they exhibit SIB. Immediately upon the occurrence of SIB, the rats will be sacrificed, and the brains will be processed for in situ hybridization of mRNA for adenosine receptors and dopamine receptors. These experiments will identify whether adaptations occur in adenosine and dopamine systems that may be implicated in onset and expression of caffeine- and pemoline-induced SIB. Furthermore, these experiments will examine whether differing neuroadaptations occur within adenosine and dopamine systems in the phenomenologically different models of SIB, and they may lay a foundation for further exploration of the molecular biology of animal models of SIB.